Use of 4-substituted tetrahydropyridines for the manufacture of medicaments acting upon TGF-beta 1

ABSTRACT

The invention relates to the use of a compound of formula (I):  
                 
 
     for the preparation of pharmaceutical compositions for increasing the circulating, cellular and extracellular levels of TGF-β1.

[0001] The present invention relates to the use of certain1,2,3,6-tetrahydropyridine derivatives, and to their pharmaceuticallyacceptable salts and solvates for the preparation of medicaments capableof increasing the levels of TGF-β1 (Transforming growth factor-β1).

[0002] TGF-β1 is a multifunctional and ubiquitous peptide which isconstituted, in its active form, by two identical sub-units linked by adisulphide bridge. As illustrated by P. Bedesse and V. Paradis (Journalof Hepatology, 1995, 22, 37-42), TGF-β1 has been identified as a factorwhich induces cell growth in transformed fibroblasts, but many othercell functions have been discovered successively.

[0003] The WO 93/09808 application describes the use of TGF-β1 for thetreatment of damages to the central nervous system.

[0004] The WO 96/34881 and WO 94/17099 applications claim novel peptideswhich have a similar activity to that of TGF-β1 and which may be usedfor the treatment of several pathologies.

[0005] TGF-β1 is for example implicated in the control of the cellcycle, in angiogenesis, in cellular differentiation, in embryogenesis,in tissue repair, as well as in apoptosis.

[0006] Amongst these activities, the anti-apoptotic effect of TGF-β1 isvery important due to its pharmacological implications.

[0007] “Apoptosis”, or “programmed cell death”, indicates the whole ofthe physiological processes linked to cell death. In its terminal phase,apoptosis is characterised by an activation of the endonucleases whichcleave double-stranded DNA in the internucleosomal regions, thusgenerating mono- and oligo-nucleosomes which complex with histones. Anenrichment in oligo- and mono-nucleosomes linked to histones is thusobserved in the cytoplasm of the apoptotic cells.

[0008] Although this phenomenon is physiological, in contrast tonecrosis, it may also be caused by pathological stimulations.

[0009] D. A. Carson and J. M. Ribeiro report (The Lancet 1993, 341,1251-1254) the role of apoptosis in certain pathologies such asimmuno-depression, immune deficiencies in patients suffering from AIDS,cell aging, and degenerative illnesses.

[0010] J. Mathieu et al. (Ann. pharmaceutiques francaises 1996, 54, 5,193-201) demonstrated that the pathological effects caused by chemicaland physical agents such as free radicals and ionising radiation arecaused by the pro-apoptotic effects of these agents.

[0011] The apoptosis-regulating products were described in the WO96/21449 patent application. The general formula includes bothinhibitors and stimulators of apoptosis, without the means ofdistinguishing them from one another being given.

[0012] It has now been found that certain tetrahydropyridines increasecirculating and cellular and extracellular levels of TGF-β1.

[0013] Thus, the object of the present invention is the use of a4-substituted 1,2,3,6-tetrahydropyridine of formula (I):

[0014] in which:

[0015] R₁ represents a halogen or a CF₃, (C₁-C₄)alkyl or (C₁-C₄)alkoxygroup;

[0016] Y represents a nitrogen atom or a CH group;

[0017] Z′ and Z″ each represent hydrogen or a (C₁-C₃)alkyl group, or onerepresents hydrogen and the other a hydroxy group, or both, together,represent an oxo group;

[0018] Z represents

[0019] a phenyl radical;

[0020] a phenyl radical monosubstituted with a substituent X, X being

[0021] a) a (C₁-C₆)alkyl; (C₁-C₆)alkoxy; (C₃-C₇)carboxyalkyl;(C₁-C₄)alkoxycarbonyl(C₁-C₆)alkyl; (C₃-C₇)carboxyalkoxy or(C₁-C₄)-alkoxycarbonyl(C₁-C₆)alkoxy group;

[0022] b) a group selected from a (C₃-C₇)cycloalkyl,(C₃-C₇)cycloalkyloxy, (C₃-C₇)cycloalkylmethyl, (C₃-C₇)cycloalkylaminoand cyclohexenyl group, it being possible for said group to besubstituted with a halogen, hydroxy, (C₁-C₄)alkoxy, carboxy,(C₁-C₄)alkoxycarbonyl, amino, mono- or di-(C₁-C₄)alkylamino;

[0023] c) a group selected from a phenyl, phenoxy, phenylamino,N-(C₁-C₃)alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl,phenylthio, phenylsulphonyl, phenylsulphinyl or styryl, it beingpossible for said group to be mono- or poly-substituted on the phenylgroup with a halogen, CF₃, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, cyano, amino,mono- or di-(C₁-C₄)alkylamino, (C₁-C₄)acylamino, carboxy,(C₁-C₄)alkoxycarbonyl, aminocarbonyl, mono- ordi-(C₁-C₄)alkylaminocarbonyl, amino(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl orhalo(C₁-C₄)alkyl;

[0024] a phenyl radical disubstituted with a substituent R₂, R₂ being ahalogen or a hydroxy, methyl, ethyl, (C₃-C₆)alkyl, (C₁-C₄)alkoxy ortrifluoromethyl group and with a substituent X, X being as definedabove;

[0025] a 1-naphthyl or 2-naphthyl radical;

[0026] a 1-naphthyl or 2-naphthyl radical substituted in positions 5, 6,7 and/or 8 with one or two hydroxyl groups, one or two (C₁-C₄)alkoxygroups or a 6,7-methylenedioxy group;

[0027] or Z″ is hydrogen and Z and Z′ represent, each independently, anon-substituted or mono-, di- or tri-substituted phenyl group;

[0028] or of one of its pharmaceutically acceptable salts and solvates,for the preparation of pharmaceutical compositions capable of increasingcirculating and cellular and extracellular levels of TGF-β₁.

[0029] According to an advantageous aspect, the object of the inventionis the use of the compound of formula (I) in which Y is CH and R₁ is o-or m-CF₃.

[0030] According to a preferred aspect, Y is CH, R₁ is o- or m-CF₃ andZ′ and Z″ are hydrogen.

[0031] According to another preferred aspect, Y is CH, R₁ is o- orm-CF₃, Z′ and Z″ represent an oxo group and Z is 4-biphenyl.

[0032] According to a further advantageous aspect, the object of theinvention is the use of the compound of formula (I) wherein Y is CH, R₁is o- or m-CF₃, Z′ and Z″ are hydrogen and Z represents a phenyl radicalmonosubstituted with a substituent X, X being a), b), c) or one of itspharmaceutically acceptable salts and solvates.

[0033] According to another preferred aspect, the invention relates tothe use of the compound of formula (I) in which Y is CH, R₁ is o- orm-CF₃, Z′ and Z″ are hydrogen and Z represents either a phenyl radicalmonosubstituted with a group X′, X′ being a phenyl non-substituted orsubstituted with 1 to 3 halogens, 1 to 3 CF₃, 1 to 3 (C₁-C₄)alkyl, 1 to3 (C₁-C₄)alkoxy, 1 to 3 cyano, 1 to 3 amino, 1 to 3 mono- ordi-(C₁-C₄)alkylamino, 1 to 3 (C₁-C₄)acylamino, 1 to 3 carboxy, 1 to 3(C₁-C₄)alkoxycarbonyl, 1 to 3 aminocarbonyl, 1 to 3 mono- ordi-(C₁-C₄)alkylaminocarbonyl, 1 to 3 amino(C₁-C₄)alkyl, 1 to 3hydroxy(C₁-C₄)alkyl or 1 to 3 halo(C₁-C₄)alkyl groups; or a phenylradical disubstituted with a substituent R₂, R₂ being a halogen or ahydroxy, methyl, ethyl, (C₃-C₆)alkyl, (C₁-C₄)alkoxy or trifluoromethylgroup and with a substituent X′, X′ being as defined above, or of one ofits pharmaceutically acceptable salts and solvates.

[0034] According to another preferred aspect, the invention relates tothe use of the compound of formula (I) in which Y is CH, R₁ is o- orm-CF₃, Z′ and Z″ are hydrogen and Z is a phenyl group substituted inpositions 3 and 4 with a (C₁-C₆)alkyl group, or of one of itspharmaceutically acceptable salts and solvates.

[0035] According to another preferred aspect, the invention relates tothe use of the compound of formula (I) in which Y is CH, R₁ is o- orm-CF₃, Z″ is hydrogen and Z and Z′, identical, each represent a phenylgroup; a phenyl group substituted in position 2, 3 or 4 with a fluorineor chlorine atom or with a methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, s-butyl, t-butyl, trifluoromethyl, cyano, methoxy, methylthio,methylsulphonyl, ethoxy, ethylthio, ethylsulphonyl,(C₁-C₃)alkoxycarbonyl or di(C₁-C₃)alkylaminocarbonyl group; a phenylgroup disubstituted in positions 2,4; 3,4; 3,5 or 2,6 with a chlorine orfluorine atom, or with a methyl, ethyl, trifluoromethyl, cyano ormethoxy group; or a phenyl group trisubstituted in positions 3,4,5;2,4,5 or 2,4,6 with a chlorine or fluorine atom, or with a methyl,ethyl, trifluoromethyl, cyano or methoxy group, or of one of itspharmaceutically acceptable salts and solvates.

[0036] According to a particularly preferred aspect, the inventionrelates to the use of the compound of formula (I) in which Y is CH, R₁is m-trifluoromethyl, Z′ and Z″ are hydrogen and Z represents anaphthyl, 6,7-dimethoxy-2-naphthyl or 6,7-methylenedioxy-2-naphthylgroup, or of one of its pharmaceutically acceptable salts and solvates.

[0037] A particularly advantageous compound according to the presentinvention may be selected amongst:

[0038]1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0039]1-[2-(6,7-dimethoxynaphth-2-yl)ethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0040]1-[2-(6,7-methylenedioxynaphth-2-yl)ethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0041]1-[2-(4-isobutylphenyl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0042]1-[(2S)-2-(4-isobutylphenyl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0043]1-[(2R)-2-(4-isobutylphenyl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0044]1-[2-(4-isobutylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0045]1-[2-(4-tertbutylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0046]1-[2-(4-isobutylphenyl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0047]1-[2-(4-isopropylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0048]1-[2-(3′-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0049]1-[2-(2′-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0050]1-[2-(4′-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0051]1-[2-(4′-fluoro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0052]1-[2-(3′-trifluoromethyl-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0053]1-[2-(4-cyclohexylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0054]1-[2-(4-biphenylyl)-2-ethyl]-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine;

[0055]1-[2-(4-biphenylyl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0056]1-[2-(4-phenoxyphenyl)-2-ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0057]1-[2-(4-benzylphenyl)-2-ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0058]1-[2-(4-n-butylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0059]1-[2-(4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0060]1-[2-(4-n-butoxyphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0061]1-[2-(3,4-diethylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetra-hydropyridine;

[0062]1-[2-(3-methyl-4-pentylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0063]1-[2-(4-methyl-3-pentylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0064]1-[2-(3,4-diethylphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;

[0065]1-(2,2-diphenylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0066] 1-[2,2-(4,4′-dichlorodiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0067]1-[2,2-(3,3′-bistrifluoromethyldiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0068]1-[2,2-(4,4′-dimethoxydiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0069]1-[2-(4-fluorophenyl)-2-phenylethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0070]1-(3,3-diphenylpropyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0071]1-[2,2-(4,4′-dichlorodiphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;

[0072]1-[2-(3′-chlorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0073]1-[2-(2′-chlorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0074]1-[2-(4′-chlorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0075]1-[2-(4-isobutylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0076]1-[2-(4-benzylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0077]1-[2-(4-cyclohexylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0078]1-[2-(4′-fluorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0079]1-[2-(4-n-butylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0080]1-[2-(biphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0081]1-[2-(4-t-butylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0082]1-[2-(4′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0083]1-[2-(2,3′-dichloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0084]1-[2-(3-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0085]1-[2-(3′,5′-dichloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0086]1-[2-(2′,4′-dichloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0087]1-[2-(2-chloro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0088]1-[2-(3′-chloro-4-biphenylyl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0089]1-[2-(2-fluoro-4-biphenylyl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0090]1-[2-(4-methoxy-3-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0091]1-[2-(4′-methoxy-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0092]1-[2-(4′-hydroxy-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0093]1-[2-(4′-ethoxycarbonylbutoxy-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0094]1-[2-(3-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0095]1-[2-(3′chloro-4′-fluoro-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0096]1-[2-(2′-trifluoromethyl-4-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0097]1-[2-(biphenyl-4-yl)ethyl]-4-(2-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0098]1-[2-(4-cyclohexenylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0099]1-[2-(3,4-diisobutylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0100]1-[2-(3,4-dipropylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0101]1-[2-(4-cyclohexylphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;

[0102]1-[2-(4-isobutylphenyl)propyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;

[0103]1-[2-(2′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0104]1-[2-(3′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

[0105] and their pharmaceutically acceptable salts and solvates.

[0106]1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,known by its laboratory code SR 57746 and its pharmaceuticallyacceptable salts and solvates, especially its hydrochloride (SR 57746A),are particularly preferred compounds for the use according to thepresent invention.

[0107] Certain compounds of formula (I) are novel products. Thus,according to another of its aspects, the present invention relates to acompound of formula (I) selected amongst:

[0108]1-[2-(6,7-methylenedioxynaphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,

[0109]1-[2-(4-cyclohexenylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,and

[0110]1-[2-(biphenyl-4-yl)ethyl]-4-(2-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,

[0111] and their pharmaceutically acceptable salts and solvates.

[0112] The salts with pharmaceutically acceptable bases are for examplethose with alkali metals or alkaline earth metals, such as sodium,potassium, calcium, magnesium, and those with organic bases, such asamines, basic amino acids (lysine, arginine, histidine), trometamol,N-methylglutamine, etc.

[0113] The salts with pharmaceutically acceptable acids are for examplethose with mineral acids, such as hydrochloride, hydrobromide, borate,phosphate, sulphate, hydrogensulphate, hydrogenphosphate, and those withorganic acids, such as citrate, benzoate, ascorbate, methylsulphate,naphthalene-2-sulphonate, picrate, fumarate, maleate, malonate, oxalate,succinate, acetate, tartrate, mesylate, tosylate, isethionate,α-ketoglutarate, α-glycerophosphate, glucose-1-phosphate, etc.

[0114] The compounds of formula (I) in which Z′ and Z″ are hydrogen or a(C₁-C₃)alkyl group are prepared as described in WO 97/01536.

[0115] The compounds of formula (I) in which one of Z′ and Z″ ishydrogen and the other is a hydroxyl, as well as the compounds in whichZ′ and Z″ together represent an oxo group, may be prepared as describedin WO 93/11107.

[0116] The compounds of formula (I) wherein Z″ is hydrogen and Z′ and Zeach represent independently a non-substituted mono-, di-, ortri-substituted phenyl group are prepared according to the followingmethod:

[0117] (a) an aryl-1,2,3,6-tetrahydropyridine of formula (II)

[0118]  in which Y and R₁ are as defined above is allowed to react withan acid of formula (III)

[0119]  in which Z and Z′ are as defined above, or with one of itsfunctional derivatives,

[0120] (b) the carbonyl intermediate of formula (IV)

[0121]  is reduced, and

[0122] (c) the compound of formula (I) thus obtained is isolated and,optionally, transformed into one of its salts or solvates.

[0123] The reaction of step (a) can be conveniently carried out in anorganic solvent at a temperature between −10° C. and the refluxtemperature of the reaction mixture; preferably the reaction is carriedout at a low temperature.

[0124] The reaction solvent used is preferably a halogenated solventsuch as methylene chloride, dichloroethane, 1,1,1-trichloroethane,chloroform and similar ones, or an alcohol such as methanol or ethanol,but other organic solvents which are compatible with the reagentsemployed, for example dioxane, tetrahydrofuran or a hydrocarbon such ashexane, may also be employed.

[0125] The reaction may conveniently be carried out in the presence of aproton acceptor, for example an alkaline carbonate or a tertiary amine.The free acid, optionally activated (with BOP for example), theanhydride, a mixed anhydride, an activated ester or an acid halide,preferably the chloride or the bromide, may be used as a suitablefunctional derivative of the acid of formula (III). Amongst theactivated esters, the p-nitrophenyl ester is particularly preferred, butthe methoxyphenyl, trityl, benzhydryl esters and similar ones are alsosuitable.

[0126] The reduction of step (b) may conveniently be carried out bysuitable reducing agents such as aluminium hydrides or a lithiumaluminium complex hydride in an inert organic solvent at a temperaturebetween 0° C. and the reflux temperature of the reaction mixtureaccording to usual techniques.

[0127] “Inert organic solvent” is understood as meaning a solvent whichdoes not interfere with the reaction. Such solvents are for exampleethers, such as diethyl ether, tetrahydrofuran, dioxane or1,2-dimethoxyethane.

[0128] The compound of formula (I) obtained is isolated according tousual techniques and optionally transformed into one of its acidaddition salts or, when an acid group is present, the amphotericcharacter of the compound enables the separation of the salts eitherwith acids or with bases.

[0129] The starting amines of formula (II) in which Y is CH are knowncompounds or may be prepared according to analogous procedures to thoseused for preparing the known compounds.

[0130] The starting amines of formula (II) in which Y is N may beprepared by the reaction of a suitable 2-halopyridine of formula (p)

[0131] in which R₁ is as defined above and Hal is a halogen atom, with a1,2,3,6-tetrahydropyridine of formula (q)

[0132] in which P° represents a protecting group such as a benzyl groupfor example, and Z represents a substituent which enables nucleophilicsubstitution of the halogen of the pyridine. Such substituents are forexample trialkylstannanes, such as tributylstannane, or Grignardcompounds.

[0133] The 1,2,3,6-tetrahydropyridine is then deprotected by cleavingthe protecting group under suitable conditions.

[0134] The acids of formula (III) may be prepared according to theWittig reaction by the reaction of a suitable benzophenone of formula(r)

[0135] in which Z and Z′ are as defined above, withtrimethylsulphoxonium iodide/BF₃-Et₂O and the oxidation of theintermediate aldehyde of formula (w)

[0136] according to the method described in J. Am. Chem. Soc., 1990.112(18):6690-6695, to obtain the corresponding acid.

[0137] According to another method, the compounds of formula (I) inwhich Z″ is hydrogen may also be prepared by the reaction of anaryl-1,2,3,6-tetrahydropyridine of formula (II)

[0138] in which R₁ and Y are as defined above, with an aldehyde offormula (w) above in the presence of a reducing agent such as sodiumcyanoborohydride, according to known techniques.

[0139] The compounds of formula (I), in which R₁ is m-trifluoromethyl, Yis CH, Z′ and Z″ are hydrogen and Z is a naphthyl group substituted withone or two alkoxy groups or with a methylenedioxy group, are prepared asdescribed in EP 0 458 697.

[0140]1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its pharmaceutically acceptable salts and solvates, especially thehydrochloride, may be prepared according to EP 0 101 381.

[0141] An advantageous method provides the reaction of2-(2-bromoethyl)naphthalene and4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and the isolationpreferably of1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride (SR 57746A) which is then crystallised in an ethanol/watermixture by heating and cooling to 5° C. with a cooling gradient of 10°C./hour and a stirring speed of 400 r.p.m., so as to obtain a mixture ofthe two crystalline forms in a ratio of about 66/34.

[0142] The1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride is preferably used in a micro-particulate form, forexample in an essentially amorphous form obtained by atomisation, or ina micro-crystalline form obtained by micronisation.

[0143] The effect of the compounds of formula (I) upon the increase ofthe levels of TGF-β1 was evaluated with the aid of tests upon the smoothmuscle cells, as well as upon the blood levels and the diaphragms in therat after administration of the representative compounds of theinvention.

[0144] Both latent TGF-β1 and activated TGF-β1 were determined on thesmooth muscle cells by incubation with hydrochloric acid.

[0145] In these tests, the representative compounds of formula (I)showed an increase in the levels of TGF-β1.

[0146] The anti-apoptotic activity was measured on the same cellsvis-à-vis the pro-apoptotic activity of a deprivation in serum or afterthe addition of toxic compounds such as vincristine or growth factorssuch as nerve growth factor (NGF) with the aid of a specific ELISA(enzyme-linked immunosorbent assay) determination kit which detects thepresence of oligonucleosomes the presence of which inside the cells is aspecific marker of programmed cell death (apoptosis), according to themethod described by Del Bino G. et al., (Experimental Cell Research,193, 27, 1991 and 195, 485, 1991) or Darzynkiewicz A et al., (Cytometry,13, 795, 1992).

[0147] In the three cases, the representative compounds of theinvention, especially:

[0148]1-[2-(3,4-diethylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine(compound A);

[0149]1-[2-(biphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine(compound B);

[0150]1-[2-(biphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine(compound C);

[0151]1-[2-(6,7-methylenedioxynaphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine(compound D);

[0152]1-[2-(4-cyclohexenylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine(compound E)

[0153]1-[2-(biphenyl-4-yl)ethyl]-4-(2-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine(compound F); and

[0154]1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine(SR 57746)

[0155] and their pharmaceutically acceptable salts, inhibit, as afunction of time and the dose, the pro-apoptotic effect induced by thedeprivation in serum or even by the addition of NGF or vincristine.

[0156] Thus, according to a further aspect, the present inventionrelates to the use of tetrahydropyridines of formula (I), of theadvantageous or preferred compounds cited above, or of theirpharmaceutically acceptable salts and solvates for the preparation of amedicament for treating diseases treatable by increasing the levels ofTGF-β1. Such pathologies are for example diseases linked to an abnormalapoptotic activity, ocular diseases such as cataracts or glaucoma,osteoporosis, bone fractures, epidermal lesions, restenosis, conditionslinked to an incorrect proliferation or migration of the smooth musclecells, inflammations of the respiratory system, asbestosis, silicosis,lupus erythematosus, Goodpasture's syndrome, granulomatosis,eosinophilic granulomatosis, gastric and duodenal ulcers, oesophagitis,enteritis, gastritis, septicaemia, dysfunctions of the haematopoiesisand/or lymphopoiesis, cystic fibrosis.

[0157] According to a particularly advantageous aspect, the presentinvention relates to the use of tetrahydropyridines of formula (I), ofthe advantageous or preferred compounds cited above, or of theirpharmaceutically acceptable salts and solvates for the preparation ofmedicaments capable of inhibiting apoptosis.

[0158] It is by virtue of this anti-apoptotic activity that thecompounds of the present invention may be used for the preparation ofmedicaments for treating cancer and its metastases, infections byantiviruses such as HIV and HTLV 1 and 2 (human immunodeficiency virusand human T lymphocyte virus) and the consequences thereof such as ATL(Adult-cell Leukaemia), leukaemia, myelopathies and arthropathies,hepatites (C, A, B, F), AIDS, immune deficiencies, cell aging, tissuedegeneration phenomena, inflammation, cell proliferation, infectiousdiseases, graft rejection, acute or chronic rheumatoid arthritis,ulcerative colitis, thrombocytopenic purpura, autoimmuneerythronoclastic anaemia, juvenile (Type I) diabetes(insulin-dependent), myelodysplasic syndrome, Huntington's disease,prion diseases, ARDS, prostatic hypertrophy, asthma, atherosclerosis andits thrombo-embolic complications, renal diseases, glomerulonephritis,ischemic pathologies such as myocardial infarction, myocardial ischemia,coronary vasospasm, angina and cardiac failure, chronic pancreatitis,auto-immune gastritis, primary biliary cirrhosis.

[0159] According to an advantageous aspect, the present inventionrelates to the use of tetrahydropyridines of formula (I), of one of theadvantageous or preferred compounds cited above, or of theirpharmaceutically acceptable salts and solvates for the preparation ofmedicaments capable of treating a disease such as graft rejection oracute or chronic rheumatoid arthritis.

[0160] According to the aim of the present invention, “treatment ofdiseases” is understood as meaning both the treatment and the preventionof the diseases, when this is possible. Thus, for example, when graftrejection is considered, the pharmaceutical compositions may be used inthe aim of prevention.

[0161] According to a further aspect, the invention relates to a methodfor increasing circulating and cellular and extracellular levels ofTGF-β1.

[0162] According to another of its aspects, the present inventionrelates to a method for inhibiting apoptosis, which comprises theadministration to a mammal in need thereof of an effective dose of acompound of formula (I), of one of the advantageous or preferredcompounds cited above, or of one of their pharmaceutically acceptablesalts and solvates, advantageously SR 57746, or one of itspharmaceutically acceptable salts and solvates.

[0163] According to a preferred aspect, SR 57746 and itspharmaceutically acceptable salts and solvates are administered in amicro-particulate form, preferably in a micro-particulate form of thehydrochloride.

[0164] The compounds of formula (I), one of the advantageous orpreferred compounds cited above or their pharmaceutically acceptablesalts and solvates are preferably administered orally.

[0165] The amount of active principle to be administered depends uponthe degree of advancement of the disease as well as the age and weightof the patient. However, the unit doses generally comprise from 0.25 to700 mg, advantageously from 0.5 to 300 mg, preferably from 1 to 150 mg,for example between 2 and 50 mg of active principle. These unit dosesare normally administered once or more times a day, preferably once tothree times per day, the overall dose in man being variable between 0.5and 1,400 mg per day, for example from 1 to 900 mg per day,advantageously from 2 to 500 mg per day, more conveniently from 2 to 200mg per day. When the active principle administered is for example SR57746, the unit dose generally comprises from 0.5 to 10 mg,advantageously from 1 to 5, preferably from 1 to 3 mg, for example1-1.5-2-2.5-3 mg of active principle. These unit doses are normallyadministered once or more times per day, preferably once to three timesper day, the overall dose in man being variable between 0.5 and 50 mgper day, for example from 1 to 20 mg per day, advantageously from 2 to10 mg per day.

[0166] The doses and amounts above refer to the compounds of formula (I)or to one of the advantageous or preferred compounds cited above, in anon-salified form.

[0167] In the pharmaceutical compositions of the present invention fororal administration, the active principle may be administered as unitforms for administration, in a mixture with classical pharmaceuticalcarriers, to mammals, to animals and to human beings for the treatmentof the above-mentioned diseases. The suitable unit forms ofadministration comprise for example tablets, which are optionallyscored, gelatine capsules, powders, granules and oral solutions orsuspensions.

[0168] When a solid composition is prepared in the form of tablets, themain active ingredient is mixed with a pharmaceutical vehicle such asgelatine, starch, lactose, magnesium stearate, talc, gum arabic oranalogues thereof. The tablets may be coated with sucrose or othersuitable materials or even they may be treated such that they have asustained or delayed activity and that they continuously release apredetermined amount of the active principle.

[0169] A gelatine capsule preparation is obtained by mixing the activeingredient with a diluant and in pouring the mixture obtained into softor hard gelatine capsules.

[0170] A preparation in the form of a syrup or elixir may contain theactive ingredient together with a sweetener, preferably an acalorificsweetener, methylparaben and propylparaben as antiseptics, as well as aflavouring agent and a suitable colouring agent.

[0171] Powders or granules which may be dispersed in water can containthe active ingredient in a mixture with dispersing agents or wettingagents, or suspension agents, such as polyvinylpyrrolidone, as well aswith sweeteners or flavour correctors.

[0172] The active principle may also be formulated in the form ofmicrocapsules, optionally with one or more carriers or additives.

[0173] In the pharmaceutical compositions according to the presentinvention, the active principle may also be in the form of an inclusioncomplex in cyclodextrins, their ethers or their esters. The PREPARATIONSand EXAMPLES below illustrate the invention better.

PREPARATION 1

[0174] 40,000 smooth muscle cells isolated from the human aorta(supplier: CLONETICS) are placed, in a 35 mm dish, in a mediumcontaining 2 ml of DMEM (Dulbecco Modified Eagle Medium containing 4.5g/l of glucose, 3.7 g/l of NaHCO₃ and not containing any L-glutamine orNa-pyruvate). 20% v/v of foetal calf serum which was desupplemented for30 min at 80° C., 4 mM L-glutamine, 50 U/ml of penicillin and 50 μg/mlof streptomycin are added. The cells are left in this medium for agrowth period of three days before submitting them to tests according tothe examples given further on.

PREPARATION 2

[0175] Dishes containing cells are prepared as described inPreparation 1. Apoptosis is induced by replacing the medium described inPreparation 1 with the same medium containing only 0.2% of foetal calfserum. The effect of the compounds of the invention upon the levels oflatent and activated TGF-β1 is measured in the extracellular media after24 hours of contact with the cells, in comparison with controls (0.2% offoetal calf serum and 20% of foetal calf serum). The activated TGF-β1 isdetermined directly in the supernatants of the culture, but the latentTGF-β1 is determined after activation. For the activation, 0.5 ml of thesupernatant of the culture are incubated in the presence of 0.1 ml of 1MHCl for 10 min. at room temperature. The mixture is then neutralisedwith 0.1 ml of 0.5 M Hepes buffer which contains 1.2 M NaOH.Determinations of TGF-β1 are carried out with the aid of a specificELISA test.

PREPARATION 3

[0176] 5 Sprague Dawley rats (Iffa Credo, France) of about 280 g weretreated every day for three days with the compound to be tested, whichwas administered orally. 24 hours after the last forced feeding, therats are anaesthetised. Blood is taken from the abdominal aorta on EDTA,the samples are centrifuged and the supernatants (plasma rich inplatelets) are frozen. The diaphragms are also taken, rinsed severaltimes in cold PBS (Phosphate buffered saline) and are centrifuged. Aftera further ultra-centrifugation the plugs are taken up into PBS andfrozen. Determinations of latent and activated TGF-β1 in the plasma andthe ground diaphragms are made by using the technique described inPREPARATION 2. The increase in the circulating latent TGF-β1 levels arerecorded in the rats treated with the compounds of the invention incomparison with control rats. The increase in the activated TGF-β1levels in the diaphragms of the rats treated with the compounds of theinvention are also recorded.

PREPARATION 4

[0177] Dishes containing the cells are prepared as in PREPARATION 1.Apoptosis is induced by three different methods:

[0178] a) by replacing the medium of PREPARATION 1 with the same mediumcontaining only 0.2% of foetal calf serum;

[0179] b) by adding increasing doses of NGF (0.01 ng/ml to 100 ng/ml) tothe medium described in PREPARATION 1;

[0180] c) by adding increasing doses of Vincristin (0.1 pg/ml to 10ng/ml) to the medium described in PREPARATION 1.

[0181] By an ELISA determination test of the mono- and oligo-nucleosomesassociated with cytoplasmic histones after washing and cellular lysis,the effects of the compounds of the invention upon the apoptosis aremeasured after 24 hours of contact with the cells in comparison with thelevels of apoptosis obtained in the absence of products (maximumapoptosis level) or in the presence of 20% foetal calf serum (minimumapoptosis level).

EXAMPLE 11-(2,2-diphenylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

[0182] 1a/1-(α,α-diphenylacetyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine.

[0183] 8 g of α,α-diphenylacetyl chloride in 50 ml of methylene chloridewere added dropwise to a mixture of 8 g (0.035 mole) of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 50 ml ofmethylene chloride and 4.96 ml of triethylamine at the temperature of0/+5° C. Stirring is effected for one hour at room temperature, thesolvent is evaporated off under reduced pressure, the residue is takenup into ethyl ether, washing is effected with a 0.2M aqueous solution ofhydrochloric acid, with water, with an aqueous solution of sodiumcarbonate and then with water. Drying is effected over sodium sulphate,the solvent is evaporated off under reduced pressure. 5 g of the titlecompound are obtained.

[0184] 1b/1-(2,2-diphenylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride.

[0185] A solution of 5 g (0.012 mole) of the product of the precedingstep in 50 ml of ethyl ether is added dropwise to a mixture of 0.7 g oflithium aluminium hydride in 10 ml of ethyl ether at 25° C. Stirring iseffected at room temperature for one hour, 5 ml of water are addeddropwise. The two phases are separated, the organic phase is dried oversodium sulphate and the solvent is evaporated off under reducedpressure.1-(2,2-diphenylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyri-dineis thus obtained. The hydrochloride is prepared with the aid of asaturated solution of hydrochloric acid in ethyl ether. Crystallisationis brought about in 150 ml of ethyl acetate. M.p. (hydrochloride)207-210° C.

EXAMPLE 21-[2,2-(4,4′-dichlorodiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its oxalate

[0186] 2a/α,α-(4,4′-dichlorodiphenyl)acetaldehyde.

[0187] 0.75 g (0.025 mole) of 80% sodium hydride in oil is addedportionwise to a mixture of 5.5 g (0.025 mole ) of trimethylsulphoxoniumiodide in 10 ml of anhydrous tetrahydrofuran. The mixture is heated at55° C. for 6 hours and 6 g (0.025 mole) of 4,4′-dichlorobenzophenone in10 ml of anhydrous tetrahydrofuran are added thereto. The mixture isleft to stir at 55° C. for one night, poured into water, extracted withethyl ether, the organic phase is dried over sodium sulphate, and thesolvent is evaporated off under reduced pressure. The residue isdissolved in 32 ml of toluene and 3 ml of BF₃-Et₂O are added thereto.The mixture is stirred for 2 minutes and is then allowed to stand for 3minutes. Washing is effected twice with an aqueous solution of sodiumbicarbonate, the organic phase is dried over sodium sulphate, and thesolvent is evaporated off under reduced pressure. An oil is obtainedwhich is purified by silica gel column chromatography in eluting with ahexane/ethyl acetate mixture=9/1. The title compound is obtained.

[0188] 2b/1-[2,2-(4,4′-dichlorodiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its oxalate.

[0189] 1.3 g (0.0045 mole) of the product of the preceding step, 1.2 g(0.0053 mole) of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,21 ml of methanol, 0.8 ml of glacial acetic acid and 0.5 g of anhydroussodium acetate are mixed at the temperature of 0/+5° C. 0.76 g (0.0121mole) of sodium cyanoborohydride is added to the mixture at the sametemperature, stirring is effected for 1.5 hours at low temperature, andthen at room temperature overnight. 5 ml of concentrated hydrochloricacid are added dropwise, stirring is continued for 10 minutes, themethanol is evaporated off and the residue is taken up in an ethylacetate/dilute aqueous NH₄OH solution mixture. The two phases areseparated, the organic phase is dried over sodium sulphate and thesolvent is evaporated off under reduced pressure. An oil is obtainedwhich is purified by silica gel column chromatography in eluting with ahexane/ethyl acetate mixture=9/1. The title compound is obtained as abase. The oxalate is prepared with the aid of oxalic acid inisopropanol. M.p. (oxalate) 187-189° C.

EXAMPLE 31-[2,2-(3,3′-bistrifluoromethyldiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its oxalate

[0190] 3a/α,α(3,3′-bistrifluoromethyldiphenyl)acetaldehyde.

[0191] In proceeding as described in Example 2a/, but by using3,3′-bistrifluoromethylbenzophenone, the title compound is obtained.

[0192] 3b/1-[2,2-(3,3′-bistrifluoromethyldiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its oxalate.

[0193] In proceeding as described in Example 2b/, but by using theproduct of the preceding step instead ofα,α-(4,4′-dichlorodiphenyl)acetaldehyde, the title compounds areobtained. M.p. (oxalate) 194-196° C.

EXAMPLE41-[2,2-(4,4′-dimethoxydiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

[0194] 4a/α,α(4,4′-dimethoxydiphenyl)acetaldehyde.

[0195] In proceeding as described in Example 2a/, but by using4,4′-dimethoxybenzophenone, the title compound is obtained.

[0196] 4b/1-[2,2-(4,4′-dimethoxydiphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride.

[0197] In proceeding as described in Example 2b/, but by using theproduct of the preceding step instead ofα,α-(4,4′-dichlorodiphenyl)acetaldehyde, the title compounds areobtained. M.p. (hydrochloride) 214-216° C.

EXAMPLE 51-[2-(4-fluorophenyl)-2-phenylethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

[0198] 5a/α-4-fluorophenyl-α-phenylacetaldehyde.

[0199] In proceeding as described in Example 2a/, but by using4-fluorobenzophenone, the title compound is obtained.

[0200] 5b/1-[2,2-(4-fluorophenyl)-2-phenylethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride.

[0201] In proceeding as described in Example 2b/, but by using theproduct of the preceding step instead ofα,α-(4,4′-dichlorodiphenyl)acetaldehyde, the title compounds areobtained. M.p. (hydrochloride) 206-208° C.

EXAMPLE 61-(3,3-diphenylpropyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride

[0202] In proceeding as described in Example 1b/ but by using commercial3,3-diphenylpropionic acid (Aldrich, reference D21,165-6) instead of2,2-diphenylacetic acid, the title compounds are obtained. M.p.(hydrochloride) 176-178° C.

EXAMPLE 71-[2,2-(4,4′-dichlorodiphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridineand its hydrochloride

[0203] In proceeding as described in Example 2b/ but by using4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine instead of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, the titlecompounds are obtained. M.p. (hydrochloride) 230-232° C.

EXAMPLE 81-[2-(3,4-diethylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0204] 8a/ 1-bromo-2-(3,4-diethylphenyl)ethane.

[0205] A mixture of 4.4 g (0.033 mole) of 3,4-diethylbenzene, 50 ml ofmethylene chloride, 8,8 g (0.044 mole) of bromoacetyl bromide is cooledto 0-5° C. and 5.0 g (0.037 mole) of aluminum trichloride are addedthereto. The mixture is stirred at 0-5° C. for one hour and is thenallowed to stand overnight at room temperature. It is poured into awater/ice mixture, extracted with methylene chloride, the organic phaseis dried over sodium sulphate and the solvent is evaporated off underreduced pressure. 2.9 g (0.011 mole) of the oil thus obtained are mixedwith 6 ml (0.079 mole) of trifluoroacetic acid and 6.7 ml (0.057 mole)of triethylsilane and the mixture is heated at 80° C. for 4 hours. Asaturated aqueous solution of sodium bicarbonate is then added up tobasic pH, extraction is effected with ethyl ether, the organic phase isdried over sodium sulphate and the solvent is evaporated off underreduced pressure. The crude oil thus obtained is purified by silica gelcolumn chromatography in eluting with cyclohexane. The title compound isobtained.

[0206] 8b/1-[2-(3,4-diethylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride.

[0207] A mixture of 2.6 g (0.001 mole) of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 60 ml ofbutanol, 4.1 g (0.025 mole) of grated anhydrous potassium carbonate and2.6 g (0.00113 mole) of the product of the preceding step is refluxedfor 5 hours. The solvent is evaporated off under reduced pressure, it istaken up into ethyl acetate, washed with water, drying is effected oversodium sulphate and the solvent is evaporated off under reducedpressure. The hydrochloride of the oil thus obtained is prepared bytreatment with a saturated solution of hydrochloric acid in isopropanol.1.6 g of the title compound are obtained M.p. 220-222° C.

EXAMPLE 91-[2-(3-methyl-4-pentylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand1-[2-(4-methyl-3-pentylphenyl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridineand their oxalates

[0208] 9a/ 1-methyl-2-pentylbenzene.

[0209] 4.7 g (0.035 mole) of phthalic aldehyde are added dropwise to asolution of 50 ml (0.1 mole) of a 2M n-butylmagnesium chloride solutionin THF under nitrogen atmosphere. The mixture spontaneously heats up to40-45° C. Stirring is effected at room temperature for one hour, themixture is poured into a saturated ammonium chloride solution, extractedwith ethyl ether, washed with water, drying is effected over sodiumsulphate and the solvent is evaporated off under reduced pressure. Theoil thus obtained is purified by silica gel column chromatography ineluting with a cyclohexane/ethyl acetate mixture=7/3. The product havingthe highest Rf is isolated. 2.0 g of oil are obtained. The crudereaction mixture is dissolved in 25 ml of ethanol and 1 ml ofconcentrated sulphuric acid and 0.15 g of 10% Pd/C are added thereto.Hydrogenation is carried out at room temperature for 7 hours. Thecatalyst is filtered off, the solvent is evaporated off under reducedpressure and the residue is taken up into ethyl acetate. The mixture iswashed with an aqueous solution of sodium bicarbonate, dried and thesolvent is evaporated off under reduced pressure. 1.35 g of the titlecompound are obtained.

[0210] 9b/ 1-bromo-2-(3-methyl-4-pentylphenyl)ethane and1-bromo-2-(4-methyl-3-pentylphenyl)ethane.

[0211] A mixture of 1.17 g (0.0054 mole) of the product of the precedingstep, 0.62 ml (0.0072 mole) of bromoacetyl bromide is cooled to 0-5° C.and 0.81 g (0.006 mole) of aluminium trichloride is added thereto.Stirring is effected at 0-5° C. for one hour and then 4 hours at roomtemperature. The mixture is poured into ice, the two phases areseparated, the organic phase is washed with water, dried and the solventis evaporated off under reduced pressure. The residue is dissolved in2.9 ml of trifluoroacetic acid and 3.1 ml (0.0267 mole) oftriethylsilane are added thereto and the mixture is heated at 80° C. for5 hours. It is poured into an aqueous solution of sodium bicarbonate andextracted with ethyl ether, washed with water and the drying is effectedover sodium sulphate. A mixture of the title compounds is obtained.

[0212] 9c/1-[2-(3-methyl-4-pentylphenyl)ethy]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand1-[2-(4-methyl-3-pentylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand their oxalates.

[0213] A mixture of 0.7 g (0.0031 mole) of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 16 ml ofbutanol, 0.9 g (0.0065 mole) of grated anhydrous potassium carbonate andthe product obtained in the preceding step (0.0054 mole theoretical) isrefluxed for 6 hours. The solvent is evaporated off under reducedpressure, the residu is taken up into ethyl acetate, washed with water,drying is effected over sodium sulphate and the solvent is evaporatedoff under reduced pressure. The oil thus obtained is purified by silicagel column chromatography in eluting with a cyclohexane/ethyl acetatemixture=7/3. Two products having similar Rfs are isolated. The producthaving the highest Rf corresponds to1-[2-(3-methyl-4-pentylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine.The oxalate is prepared in acetone. 0.12 g of product is obtained. M.p.140-143° C. The product having the lowest Rf corresponds to the1-[2-(4-methyl-3-pentylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineisomer. The oxalate is prepared in acetone. Crystallisation of theproduct is brought about in acetone. 0.08 g of product is obtained. M.p.167-169° C.

EXAMPLE 101-[2-(3,4-diethylphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridinehydrochloride

[0214] 10a/(1-benzyl-1,2,3,6-tetrahydropyrid-4-yl)tributylstannane.

[0215] A mixture of 15.85 g (0.0837 mole) of 1-benzyl-4-piperidone in140 ml of anhydrous dimethoxyethane and 25 g (0.0837 mole) oftrisilidrazine in 140 ml of anhydrous dimethoxyethane is stirred at roomtemperature for 3 hours. The solvent is evaporated off under reducedpressure. The residue is taken up into 420 ml of anhydrous hexane and420 ml of anhydrous tetramethylethylenediamine are added thereto. Themixture is cooled to −78° C. and 156 ml of n-butyllithium (0.25 mole)(1.6 M solution in hexane) are added dropwise thereto. After about 30minutes the temperature is allowed to attain 0° C. and stirring iseffected for 15 minutes. 45 ml (0.167 mole) of tributylstannyl chlorideare then added to the reaction mixture. After 1 hour, a water/icemixture is added with extreme caution. Extraction is carried out withethyl ether, the organic phase is washed with water, drying is effectedover sodium sulphate and the solvent is evaporated off under reducedpressure. 70 g of crude product are obtained which are purified bysilica gel column chromatography in eluting with a cyclohexane/ethylacetate mixture=95/5. The title compound is obtained as an oil.

[0216]¹H-NMR (CDCl₃)-δ (ppm): 0.84 (9H; m: CH₃); 1.19-1.58 (18H; m:CH₂-chain); 2.31 (2H; m); 2.53 (2H; m); 3.02 (2H; m); 3.56 (2H; s:benzylic methylene); 5.76 (1H; m*); 7.18-7.41 (5H; m: arom.) * sidebands ³Jcis(¹H-¹¹⁷Sn) and ³Jcis(¹H-¹¹⁹Sn).

[0217] 10b/ 1-benzyl-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine.

[0218] 18.5 g (0.04 mole) of the compound of the preceding step aredissolved in 200 ml of anhydrous dimethylfonnamide under nitrogenatmosphere. 11.8 g (0.08 mole) of 2,6-dichloropyridine, 0.64 g of Pd(II)(Ph₃P)₂Cl₂, 4.38 g (0.04 mole) of tetraethylammonium chloride and 2.76 g(0.02 mole) of potassium carbonate are added to the solution. Themixture is heated at 110° C. for 6 hours and is then poured into 100 mlof a 5% sulphuric acid solution. Extraction is carried out with ethylether, ammonium hydroxide is added to the aqueous phase up to basic pHand extraction is carried out with ethyl acetate. The combined organicphases are dried over sodium sulphate and the solvent is evaporated offunder reduced pressure. The residue is purified by silica gel columnchromatography in eluting with a cyclohexane/ethyl acetate mixture=1/1.The title compound is obtained. M.p. 100-102° C.

[0219] 10c/ 4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridinehydrochloride.

[0220] A solution of 7.0 g (0.024 mole) of the compound of the precedingstep in 110 ml of dichloroethane is cooled to 0-5° C. and 5.8 ml (0.054mole) of chloroethyl chloroformate are added thereto. Stirring iseffected for 5 minutes and then refluxing is effected for 1.5 hours. Thesolvent is evaporated off under reduced pressure, the residue is takenup in 100 ml of methanol and heating under reflux is effected for 1hour. The solvent is evaporated off, the residue is taken up inisopropanol and the solid is filtered off. The title compound isobtained which is crystallised in 90% ethanol. M.p. 305-307° C.

[0221] 10d/1-[2-(3,4-diethylphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridinehydrochloride.

[0222] In proceeding as described in Example 8b/ but by using theproduct of the preceding step instead of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, the titlecompound is obtained. M.p. 234-236° C.

EXAMPLES 11-20

[0223] In proceeding as described in Example 9 but by using theappropriate magnesium halide, the following compounds are obtained:

[0224]1-[2-(3-ethyl-4-methylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine—Ex.11

[0225]1-[2-(4-ethyl-3-methylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine—Ex.12

[0226]1-[2-(3-ethyl-4-propylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine—Ex.13

[0227]1-[2-(4-ethyl-3-propylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine—Ex.14

[0228]1-[2-(3-butyl-4-methylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine—Ex.15

[0229]1-[2-(4-butyl-3-methylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine—Ex.16

[0230]1-[2-(3-isobutyl-4-methylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine—Ex.17

[0231]1-[2-(4-isobutyl-3-methylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine—Ex.18

[0232]1-[2-(3-isobutyl-4-ethylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine—Ex.19

[0233]1-[2-(4-isobutyl-3-ethylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine—Ex.20

EXAMPLE 211-[2-(6-methyl-3-biphenylyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine

[0234] In proceeding as described in Example 9 but by usingphenyllithium instead of n-butylmagnesium chloride, the title compoundis obtained.

EXAMPLE 221-[2-(3′-chlorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0235] 22a/ 1-bromo-2-(3′-chlorobiphenyl-4-yl)ethanone.

[0236] A mixture of 5 g (0.026 mole) of 3-chlorobiphenyl, 50 ml ofmethylene chloride, 6.95 g (0.034 mole) of bromoacetyl bromide is cooledto 0-5° C. and 4 g (0.030 mole) of aluminium trichloride are addedthereto. Stirring is effected for 1 hour at 5° C. and then 4 hours atroom temperature. The mixture is poured into a water/ice mixture,extracted with methylene chloride, the organic phase is washed with a 1NHCl solution, drying is effected over sodium sulphate and the residu isevaporated under reduced pressure. 4.5 g of the title compound areobtained. M.p. 63-65° C.

[0237] 22b/1-[2-(3′-chlorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride.

[0238] A mixture of 0.4 g (0.013 mole) of the product of the precedingstep, 2.95 g (0.013 mole) of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 80 ml of ethanoland 2.32 g (0.0167 mole) of grated anhydrous potassium carbonate isrefluxed for 1 hour. The salts are removed by filtering and the solutionis acidified by the addition of a saturated solution of hydrochloricacid in ethanol. Concentration is carried out under reduced pressureuntil about 40 ml and the residu is allowed to stand overnight at 5° C.The precipitate is filtered off, washed with water and then withisopropanol. 4.9 g of the title compound are obtained. M.p. 217-220° C.

EXAMPLE 231-[2-(2′-chlorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0239] In proceeding as described in Example 22 but by using2-chlorobiphenyl instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 200-202° C. (crystallised in isopropanol).

EXAMPLE 241-[2-(4-chlorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0240] In proceeding as described in Example 22 but by using4-chlorobiphenyl instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 210-215° C.

EXAMPLE 251-[2-(4-isobutylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0241] In proceeding as described in Example 22 but by using4-isobutylbenzene instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 224-228° C. (crystallised in isopropanol).

EXAMPLE 261-[2-(4-phenoxyphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0242] In proceeding as described in Example 22 but by using diphenylether instead of 3-chlorobiphenyl, the title compound is obtained. M.p.205-210° C.

EXAMPLE 271-[2-(4-cyclohexylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0243] In proceeding as described in Example 22 but by usingcyclohexylbenzene instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 209-213° C. (crystallised in isopropanol).

EXAMPLE 281-[2-(4′-fluorobiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0244] In proceeding as described in Example 22 but by using4-fluorobiphenyl instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 123-125° C. (crystallised in isopropanol).

EXAMPLE 291-[2-(biphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0245] In proceeding as described in Example 22 but by using biphenylinstead of 3-chlorobiphenyl, the title compound is obtained. M.p.145-147° C. (base); M.p. 240-243° C. (hydrochloride).

EXAMPLE 301-[2-(4-n-butylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0246] In proceeding as described in Example 22 but by using4-n-butylbenzene instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 218-221° C.

EXAMPLE 311-[2-(4-t-butylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0247] In proceeding as described in Example 22 but by using4-t-butylbenzene instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 97-99° C. (base).

EXAMPLE 321-[2-(3,4-diethylphenyl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0248] In proceeding as described in Example 22 but by using3,4-diethylbenzene instead of 3-chlorobiphenyl, the title compound isobtained. M.p. 232-234° C.

EXAMPLE 331-[2-(2′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0249] 33a/ 2-(4-bromophenyl)-2,2-dimethoxyethane.

[0250] A mixture of 2 g (0.01 mole) of 4-bromoacetophenone, 5.6 ml oftrimethyl orthoformate, 5.6 ml of methanol and 0.67 g of Amberlite® IR120 is refluxed for three hours. After cooling, it is filtered through,Celite® and the filtered solution is evaporated. 2.4 g of the titleproduct are obtained as an oil.

[0251] 33b/ 2,2-dimethoxy-2-(2′-trifluoromethylbiphenyl-4-yl)ethane.

[0252] A mixture of 4.9 g (14 mmole) of the product of the precedingstep, 2.45 g (16 mmole) of 2-trifluoromethylbenzeneboronic acid, 63 mg(0.28 mmole) of palladium acetate, 4.84 g (35 mmole) of potassiumcarbonate and 4.5 g (14 mmole) of tetrabutylammonium bromide in 19 ml ofwater is stirred at 70° C. for 1 hour. It is left to cool and it isextracted with ethyl acetate. The organic phase is dried over sodiumsulphate, filtered and the solvent is evaporated under reduced pressure.The title compound is obtained as an oil.

[0253] 33c/ 4-(2-trifluorophenyl)acetophenone.

[0254] A solution of 4 ml of trifluoroacetic acid and 4 ml of water isadded to a solution of 4.6 g (0.0105 mole) of the product of thepreceding step in 4 ml of methylene chloride at 0° C. The mixture isstirred at room temperature for 2 hours, is poured into water andextracted with methylene chloride. The organic phase is dried, filteredand the solvent is evaporated off under reduced pressure. The crude ispurified by silica gel column chromatography in eluting with acyclohexanelethyl acetate mixture=9/1. 1.97 g of the title product areobtained.

[0255] 33d/α-bromo-4-(2-trifluoromethylphenyl)acetophenone.

[0256] 0.38 ml (7.5 mmole) of bromine is added dropwise to a solution of1.97 g (7.5 mmole) of the product of the preceding step in 5.4 ml ofmethanol, at a temperature of 0° C. Stirring is effected at roomtemperature for 3 hours, the solvent is evaporated and the residue istaken up into water and extracted with ethyl acetate. The organic phaseis dried over sodium sulphate, filtered and the solvent is evaporatedoff under reduced pressure. The title product is obtained as an oil.

[0257] 33e/1-[2-(2′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride.

[0258] A mixture of 0.74 g (0.0028 mole) of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 14 ml of ethanoland 1.27 g (0.0092 mole) of grated anhydrous potassium carbonate isrefluxed for 1 hour. A solution of 1.2 g (0.0035 mole) of the oil of thepreceding step in 3 ml of ethanol is added thereto and the mixture isleft under reflux for 30 minutes. The salts are removed by filtration,and the solution is acidified by the addition of a 1 M aqueoushydrochloric acid solution. The solvent is evaporated off under reducedpressure, extraction is carried out with chloroform, and the organicphase is dried over sodium sulphate, filtered and the solvent isevaporated off under reduced pressure. The base is released with the aidof a concentrated solution of ammonia, is extracted with ethyl acetate,and the product is purified by silica gel column chromatography ineluting with a cyclohexane/ethyl acetate mixture=8/2. The title compoundis obtained. The hydrochloride is prepared with the aid of a saturatedsolution of hydrochloric acid in isopropanol. M.p. 195-197° C.

EXAMPLE 341-[2-(3′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0259] In proceeding as described in Example 33 but by using3-trifluoromethyl-benzeneboronic acid instead of2-trifluoromethylbenzeneboronic acid in step 33b/, the title compound isobtained. M.p. 232-234° C.

EXAMPLE 351-[2-(4′-trifluoromethylbiphenyl-4-yl)-2-oxoethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0260] In proceeding as described in Example 33 but by using4-trifluoromethylbenzene-boronic acid instead of2-trifluoromethylbenzeneboronic acid in step 33b/, the title compound isobtained. M.p. 245-247° C.

EXAMPLE 36

[0261] A mixture of 12.5 g of 2-(2-bromoethyl)naphthalene, 14 g of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride,4.34 g of sodium hydroxide, 135 ml of water and 95 ml of 95% ethanol isheated for 5 hours under reflux, and the reaction mixture is then leftto cool overnight to room temperature. The mixture is cooled to below25° C., and then is filtered, the product thus isolated is washed withwater and then dried in vacuo at 50° C.1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinebase is thus obtained in a yield of 90% calculated on the starting4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride.

EXAMPLE 37

[0262] A mixture of 19.5 g of crude1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride, 95 ml of absolute ethanol and 4.65 ml of 37% hydrochloricacid is heated under reflux with stirring until complete dissolution,and is then left to cool whilst the stirring is continued. When thefirst crystals start to form (about 63° C.), the stirring is stopped andthe reaction mixture is maintained at 0-5° C. overnight. Afterfiltering, the product is swollen twice in 30 ml of absolute ethanol,and then dried overnight at 40° C. in vacuo.

[0263] Under these conditions, 12.8 g of Form I of1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride are obtained.

[0264] The differential calorimetric analysis of Form I obtained in thispreparation shows

[0265] a solid-solid transition temperature of 148-149° C.

[0266] a transition enthalpy of 26.4 J/g.

EXAMPLE 38

[0267] A mixture of 70 g of crude1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride and 1 l of absolute ethanol is refluxed in a Mettler RC1calorimetric reactor equipped with an impeller of 8 cm in diameter untilcomplete dissolution of the product. The solution thus obtained iscooled with a cooling rate of 80° C. per hour and a stirring speed of500 r.p.m.to 10° C. The precipitate thus obtained is filtered and driedovernight at 45° C. in vacuo. Under these conditions, Form II of1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride is obtained.

[0268] The differential calorimetric analysis of Form II obtained inthis preparation shows

[0269] a solid-solid transition temperature of 153-155° C.

[0270] a transition enthalpy of 24.1 J/g.

EXAMPLE 39

[0271] A mixture of 2 g of1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride and 50 ml of dimethylsulphoxide is refluxed until completedissolution, it is left to cool overnight, and then the crystallineproduct is recovered and dried in vacuo at 45° C. overnight.

[0272] Under these conditions, Form III of1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride is obtained.

[0273] The differential calorimetric analysis of Form III obtained inthis preparation shows

[0274] a solid-solid transition temperature of 141-142° C.

[0275] a transition enthalpy of 17.6 J/g.

EXAMPLE 40

[0276] A mixture of 100 g of1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride in 11 of an ethanol/water mixture 90/10 is refluxed withstirring until complete dissolution of the product. The solution thusobtained is cooled from the reflux temperature to 5° C. under impellerstirring at 400 r.p.m. at a cooling speed of 10° C./hour. Thecrystalline product thus obtained is filtered and dried at 45° C. invacuo overnight.

[0277] Under these conditions,1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride is obtained as a mixture of Form I/Form III, in a ratio of65.7/34.3.

[0278] The differential calorimetric analysis of Form I/III obtained inthis preparation shows a thermogram which shows only the twocharacteristic peaks corresponding to Forms I and III.

EXAMPLE 41

[0279] A solution of 3 g of1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride in 300 ml of ethanol is atomised in a “Büchi mini SprayDryer” apparatus according to the principal of atomisation by parallelcurrent pipe, in regulating the flow rate of the pump, the suction, theheating and the current flow so as to have an entry temperature of 172°C., an exit temperature of 107° C. and a depression of 40 mbar. Underthese conditions, a wide DSC monopeak product is obtained with themaximum at 145° C. The particles obtained are spherical and the veryhomogenous population does not exceed 5 micrometres in average size.

EXAMPLE 42

[0280] 24 kg of1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride—Form I/III, described in Example 40, are introduced intothe micronisation chamber (200 mm diameter) of an Alpine 200 ASmicroniser at a speed of 25 kg/hour and at a working pressure of 6.5bars and the product thus micronised is recovered in a filter sleeve. Amicronised product is thus obtained which has a particle distributionaccording to which the whole of the particles has a size of less than 20micrometres and 85% of the particles have a size of less than 10micrometres.

[0281] The differential calorimetric analysis of the micronised productthus obtained shows that the transition temperatures are not affected bymicronisation. Said transitions are of the solid-solid type. Thecompound degrades before melting, which starts at 250° C.

EXAMPLE 43

[0282] A pharmaceutical composition which contains, as active principle,1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride Form I/III (micronised) according to Example 42 above:Active principle  2.192 mg Corn Starch 141.208 mg MicrocrystallineCellulose  26.000 mg Anhydrous colloidal Silica  0.200 mg MagnesiumStearate  0.400 mg

[0283] The active principle is sieved at 0.2 mm, and then premixed withthe excipients. This mixture is sieved at 0.315 mm, remixed, and thensieved again at 0.315 mm. After a final mixing, the composition isintroduced into gelatine capsules No. 3, at the rate of 170 mg of thecomposition containing an amount of1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride—Form I/III which corresponds to 2 mg of1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinebase.

EXAMPLE 44

[0284] Dishes containing cells are prepared as in PREPARATION 1. Thelevels of TGF-β1 are measured as described in PREPARATION 2. The levelsof activated TGF-β1 are measured in the extracellular media in thepresence of SR 57746A after 1, 3, 14, 24 and 48 hours and 7 days ofcontact with the cells, in comparison with the controls (0.2% foetalcalf serum and 20% foetal calf serum) by the method described inPREPARATION 2. SR 57746 induces a significant increase in the levels ofactivated TGF-β1 in the extracellular media after 14 hours of contactwith the cells.

EXAMPLE 45

[0285] Dishes containing cells are prepared as in PREPARATION 1 andapoptosis is induced as in PREPARATION 4 according to method a). Theanti-apoptotic effects of SR 57746 and compounds A, B, C, D, E and F aremeasured after 1, 3, 14, 24, 48 hours and 7 days of contact with thecells in comparison with the controls (0.2% foetal calf serum and 20%foetal calf serum) by the method described in PREPARATION 4.

[0286] The compounds tested significantly inhibit the apoptosis inducedby deprivation of serum after 24 hours of contact with the cells and for7 days at least.

EXAMPLE 46

[0287] Dishes containing cells are prepared as in PREPARATION 1.Apoptosis is induced according to method b) of PREPARATION 4. Theapoptosis levels are measured after 24 hours of contact with the cellsby the method described in PREPARATION 4; the same controls as inPREPARATION 4 are used. SR 57746 as well as compounds A, B, C, D, E andF significantly inhibit the pro-apoptotic effect of NGF.

EXAMPLE 47

[0288] Dishes containing cells are prepared as described inPREPARATION 1. Apoptosis is induced according to method c) ofPREPARATION 4. The levels of apoptosis are measured after 24 hours ofcontact with the cells by the method described in PREPARATION 4; thesame controls as in PREPARATION 4 are used. SR 57746 and compounds A, B,C, D, E and F significantly inhibit the proapoptotic effect ofvincristine.

EXAMPLE 481-1-[2-(6,7-methylenedioxynaphth-2-yl)ethyl]-4-[3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0289] 1.1 g (0.0048 mole) of 2-(6,7-dimethoxynaphth-2-yl)acetic acid,20 ml of methylene chloride, 2 ml (0.0144 mole) of triethylamine, 1.35 g(0.0048 mole) of 4-(3-trifluoromethylphenyl)-4-piperidinol and 2.15 g(0.0048 mole) of BOP are stirred at room temperature. Washing iseffected with a 1 N HCl solution, and then with a saturated solution ofNaHCO₃ and then with water. Drying is effected over sodium sulphate andthe solvent is evaporated off under reduced pressure. 1.5 g of the oilthus obtained are dissolved in 18 ml of THEF. The mixture is heated atreflux and a solution of 0.97 ml (0.0102 mole) ofdimethylsulphide/borane in 12 ml of THF is added dropwise thereto. Themixture is refluxed for 4 hours, cooled to 0° C. and 15 ml of methanolare added. It is heated again at reflux for 30 min, and then evaporatedunder reduced pressure. The residue is taken up into ethyl acetate,washed with water, dried over sodium sulphate and evaporated underreduced pressure. The oil obtained is dissolved in 22 ml of glacialacetic acid, and 1,2 ml of concentrated sulphuric acid are addedthereto, and the mixture is heated at 60° C. for 4 hours. It is pouredinto an ice/NaOH mixture and is extracted with ethyl acetate. Thehydrochloride is prepared with the aid of isopropanol saturated with HClin obtaining the title compound M.p. 277-280° C.

EXAMPLE 49

[0290] 49a/ 4-(2-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride.

[0291] A mixture of 2 g (0.0071 mole) of4-(2-trifluoromethylphenyl)-4-piperidinol (prepared frombenzylpiperidone, 2-bromo-1-trifluoromethylbenzene and magnesium andsuccessive hydrogenation), 12 ml of glacial acetic acid and 3 ml ofconcentrated sulphuric acid is heated at 100° C. for 2 hours. It ispoured into an ice/NaOH mixture and is extracted with methylenechloride. The organic phase is dried and evaporated under reducedpressure. The hydrochloride is prepared with the aid of isopropanolsaturated with hydrochloric acid. M.p. 213-215° C.

[0292] 49b/1-[2-(biphenyl-4-yl)ethyl]-4-(2-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride.

[0293] In proceeding as described in Example 8b but by using the productof the preceding step instead of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and1-bromo-2-biphenylylethane instead of the product of step 8a, the titlecompound is obtained. M.p. 273-275° C.

EXAMPLE 501-[2-(4-cyclohexenylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

[0294] A mixture of 1 g (0.005 mole) of 2-(4-bromophenyl)ethanol, 0.7 g(0.0055 mole) of 1-cyclohexeneboronic acid, 25 mg of palladium acetate,1.73 g (0.0012 mole) of potassium carbonate and 1.61 g (0.005 mole) oftetrabutylammonium bromide in 7 ml of water is stirred at 70° C. for 3hours. It is left to cool and is extracted with ethyl acetate. Theorganic phase is dried over sodium sulphate, filtered and the solvent isevaporated under reduced pressure. The reaction crude is purified bysilica gel column chromatography, in eluting with a cyclohexane/ethylacetate mixture=7/3. The title compound is obtained as an oil. Asolution of 1.35 g (6.67 mmoles) of the product of the preceding step,0.93 ml (6.67 moles) of mesyl chloride in 0.5 ml of methylene chloride,is cooled to 0.5° C. The mixture is stirred at 0° C. for 30 minutes andthen overnight at room temperature. The mixture is poured into water andis extracted with methylene chloride. The organic phase is dried and thesolvent is evaporated off under reduced pressure. The residue is takenup into 8 ml of isopropanol, and 0.64 ml (4.6 mmoles) of triethylamineand 0.45 g (1.7 mmoles) of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine are addedthereto. The mixture is refluxed for 4 hours, the solvent is evaporatedoff and is washed with water. It is extracted with methylene chloride,the organic phase is dried and the solvent is evaporated off underreduced pressure. The residue is purified by silica gel columnchromatography in eluting with a cyclohexane/ethyl acetate mixture=8/2.The hydrochloride is prepared with the aid of isopropanol saturated withHCl. The title compound is obtained. M.p. 244-245° C.

1. Use of a compound of formula (I):

in which: R₁ represents a halogen or a CF₃, (C₁-C₄)alkyl or(C₁-C₄)alkoxy group; Y represents a nitrogen atom or a CH group; Z′ andZ″ each represent hydrogen or a (C₁-C₃) alkyl group, or one representshydrogen and the other a hydroxy group, or both, together, represent anoxo group; Z represents a phenyl radical; a phenyl radicalmonosubstituted with a substituent X, X being a) a (C₁-C₆)alkyl;(C₁-C₆)alkoxy; (C₃-C₇)carboxyalkyl; (C₁-C₄)alkoxycarbonyl(C₁-C₆)alkyl;(C₃-C₇)carboxyalkoxy or (C₁-C₄)-alkoxycarbonyl(C₁-C₆)alkoxy group; b) agroup selected from a (C₃-C₇)cycloalkyl, (C₃-C₇)cycloalkyloxy,(C₃-C₇)cycloalkylmethyl, (C₃-C₇)cycloalkylamino and cyclohexenyl group,it being possible for said group to be substituted with a halogen,hydroxy, (C₁-C₄)alkoxy, carboxy, (C₁-C₄)alkoxycarbonyl, amino, mono- ordi-(C₁-C₄)alkylamino; c) a group selected from a phenyl, phenoxy,phenylamino, N-(C₁-C₃)alkylphenylamino, phenylmethyl, phenylethyl,phenylcarbonyl, phenylthio, phenylsulphonyl, phenylsulphinyl or styryl,it being possible for said group to be mono- or poly-substituted on thephenyl group with a halogen, CF₃, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, cyano,amino, mono- or di-(C₁-C₄)alkylamino, (C₁-C₄)acylamino, carboxy,(C₁-C₄)alkoxycarbonyl, aminocarbonyl, mono- ordi-(C₁-C₄)alkylaminocarbonyl, amino(C₁-C₄)alkyl, hydroxy(C₁-C₄)alkyl orhalo(C₁-C₄)alkyl; a phenyl radical disubstituted with a substituent R₂,R₂ being a halogen or a hydroxy, methyl, ethyl, (C₃-C₆)alkyl,(C₁-C₄)alkoxy or trifluoromethyl group and with a substituent X, X beingas defined above; a 1-naphthyl or 2-naphthyl radical; a 1-naphthyl or2-naphthyl radical substituted in positions 5, 6, 7 and/or 8 with one ortwo hydroxyl groups, one or two (C₁-C₄)alkoxy groups or a6,7-methylenedioxy group; or Z″ is hydrogen and Z and Z′ represent, eachindependently, a non-substituted or mono-, di- or tri-substituted phenylgroup; or of one of its pharmaceutically acceptable salts and solvates,for the preparation of pharmaceutical compositions capable of increasingcirculating and cellular and extracellular levels of TGF-β₁.
 2. Useaccording to claim 1, characterised in that in said compound of formula(I), Y is CH and R₁ is o- or m-CF₃.
 3. Use according to claim 2,characterised in that Z′ and Z″ are hydrogen.
 4. Use according to claim2, characterised in that Z′ and Z″ together form an oxo group and Z is4-biphenyl.
 5. Use according to claim 3, characterised in that Zrepresents a 2-naphthyl, 6,7-dimethoxy-2-naphthyl or6,7-methylenedioxy-2-naphthyl group.
 6. Use according to claim 3,characterised in that Z represents a phenyl radical monosubstituted witha substituent X, X being as defined in claim
 1. 7. Use according toclaim 3, characterised in that Z represents a phenyl radicalmonosubstituted with a group X′, X′ being a phenyl, non-substituted orsubstituted with 1 to 3 halogens, 1 to 3 CF₃, 1 to 3 (C₁-C₄)alkyl, 1 to3 (C₁-C₄)alkoxy, 1 to 3 cyano, 1 to 3 amino, 1 to 3 mono- ordi-(C₁-C₄)alkylamino, 1 to 3 (C₁-C₄)acylamino, 1 to 3 carboxy, 1 to 3(C₁-C₄)alkoxycarbonyl, 1 to 3 aminocarbonyl, 1 to 3 mono- ordi-(C₁-C₄)alkylaminocarbonyl, 1 to 3 amino(C₁-C₄)alkyl, 1 to 3hydroxy(C₁-C₄)alkyl or 1 to 3 halo(C₁-C₄)alkyl groups; or a phenylradical disubstituted with a substituent R₂, R₂ being as defined inclaim 1 and with a substituent X′, X′ being as defined above.
 8. Useaccording to claim 3, characterised in that Z is a phenyl groupdisubstituted in positions 3 and 4 with a methyl, ethyl or (C₃-C₆) alkylgroup.
 9. Use according to claim 2, characterised in that Z″ is hydrogenand Z and Z′, identical, each represent a phenyl group; a phenyl groupsubstituted in position 2, 3 or 4 with a fluorine or chlorine atom orwith a methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl,t-butyl, trifluoromethyl, cyano, methoxy, methylthio, methylsulphonyl,ethoxy, ethylthio, ethylsulphonyl, (C₁-C₃)alkoxycarbonyl ordi(C₁-C₃)alkylaminocarbonyl group; a phenyl group disubstituted inpositions 2,4; 3,4; 3,5 or 2,6 with a chlorine or fluorine atom, or witha methyl, ethyl, trifluoromethyl, cyano or methoxy group; or a phenylgroup trisubstituted in positions 3,4,5 ; 2,4,5 or 2,4,6 with a chlorineor fluorine atom, or with a methyl, ethyl, trifluoromethyl, cyano ormethoxy group.
 10. Use according to claim 3, characterised in that thecompound of formula (I) is1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride.
 11. Use according to claim 10, characterised in that the1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride is atomised or micronised.
 12. Use according to claim 10,characterised in that the1-[2-(2-naphthyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride is a micronised mixture of crystalline forms I and III ina ratio of about 66/34.
 13. Use according to one of claims 1 to 12,characterised in that the pharmaceutical compositions are indicated forthe treatment of diseases treatable by increasing circulating andcellular and extracellular levels of TGF-β1.
 14. Use according to claim13, characterised in that the pharmaceutical compositions are indicatedfor the treatment of diseases selected from pathologies linked to anabnormal apoptotic activity; ocular diseases such as cataracts orglaucoma; osteoporosis; bone fractures; epidermal lesions; restenosis;conditions linked to an incorrect proliferation or migration of thesmooth muscle cells; inflammations of the respiratory system;asbestosis; silicosis; lupus erythematosus; Goodpasture's syndrome;granulomatosis; eosinophilic granulomatosis; gastric and duodenalulcers; oesophagitis; enteritis; gastritis; septicaemia; dysfunctions ofthe haematopoiesis and/or lymphopoiesis; and cystic fibrosis.
 15. Useaccording to claim 13, characterised in that the pharmaceuticalcompositions are indicated for the treatment of pathologies linked to anabnormal apoptotic activity.
 16. Use according to claim 15,characterised in that the pharmaceutical compositions are indicated forthe treatment of a disease selected from cancer and its metastases;infections by antiviruses such as HIV and HITV 1 and 2 and theconsequences thereof such as ATL; leukaemia; myelopathies andarthropathies; hepatites (C, A, B, F); AIDS; immune deficiencies; cellaging; tissue degeneration phenomena; inflammation; cell proliferation;infectious diseases; graft rejection; acute or chronic rheumatoidarthritis; ulcerative colitis; thrombocytopenic purpura; autoimmuneerythronoclastic anaemia; juvenile (Type I) diabetes(insulin-dependent); myelodysplasic syndrome; Huntington's disease;prion diseases; ARDS; prostatic hypertrophy; asthma; atherosclerosis andits thrombo-embolic complications; renal diseases, glomerulonephritis,chronic pancreatitis, auto-immune gastritis, primary biliary cirrhosis.17. Use according to claim 16, characterised in that the pharmaceuticalcompositions are indicated for the treatment of graft rejection or ofacute or chronic rheumatoid arthritis.
 18. Use according to claim 15 ofa compound of formula (I) other than compounds wherein Z′ and Z″ eachrepresent hydrogen and Z represents 1-naphthyl or 2-naphthyl for thepreparation of a medicament capable of treating myocardial infarction,myocardial ischaemia, coronary vasospasm, angina and cardiac failure.19. A compound selected from1-[2-(6,7-methylenedioxynaphth-2-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,1-[2-(4-cyclohexenylphenyl)-ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand1-[2-(biphenyl-4-yl)ethyl]-4-(2-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand their pharmaceutically acceptable salts and solvates.